Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus
Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damag...
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| Format: | Article |
| Language: | English |
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Wiley
2023-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2023/4743975 |
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| author | Xinai Han Xiaoming Zhang Rui Song Shiqi Li Shujing Zou Quanguang Tan Tianyang Liu Shugeng Luo Zhe Wu Hongyu Jie Jinhong Wang |
| author_facet | Xinai Han Xiaoming Zhang Rui Song Shiqi Li Shujing Zou Quanguang Tan Tianyang Liu Shugeng Luo Zhe Wu Hongyu Jie Jinhong Wang |
| author_sort | Xinai Han |
| collection | DOAJ |
| description | Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damage the vascular endothelium and aggravate vascular inflammation, which is considered an important pathogenic factor of DAH in SLE. Therefore, blocking the release of NETs from neutrophils is an important target for the treatment of DAH in SLE. In this study, we investigated whether the inhibition of neutrophils releasing NETs could relieve DAH in SLE. Necrostatin-1 (Nec-1), a small molecule, has been reported to inhibit the release of NETs by neutrophils. In vitro experiments revealed that Nec-1 inhibited alveolar epithelial cell damage by preventing the release of NETs. Furthermore, vivo studies showed that Nec-1 alleviated lupus pulmonary haemorrhage in mice by reducing lung pathology severity, body weight, and serum inflammatory cytokine levels. Mechanistically, Nec-1 prevented NET release by inhibiting neutrophil elastase (NE) activation and N-Gasdermin D (N-GSDMD) expression. Additionally, immunohistochemistry and immunofluorescence findings showed that Nec-1 decreased NE expression in the lung tissues of mice with lupus pulmonary haemorrhage. Thus, NETs released by neutrophils contributed to the pathogenesis of DAH in SLE, and Nec-1 showed protective effects by the inhibition of NET production via the reduction of NE activation and N-GSDMD expression. |
| format | Article |
| id | doaj-art-3f68aaa951a9430c8f0b1e809c426e05 |
| institution | Kabale University |
| issn | 2314-7156 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-3f68aaa951a9430c8f0b1e809c426e052025-02-03T06:47:30ZengWileyJournal of Immunology Research2314-71562023-01-01202310.1155/2023/4743975Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine LupusXinai Han0Xiaoming Zhang1Rui Song2Shiqi Li3Shujing Zou4Quanguang Tan5Tianyang Liu6Shugeng Luo7Zhe Wu8Hongyu Jie9Jinhong Wang10Department of Rheumatology and ImmunologyProvincial Key Laboratory of Bone and Joint Degeneration DiseasesDepartment of Rheumatology and ImmunologyProvincial Key Laboratory of Bone and Joint Degeneration DiseasesProvincial Key Laboratory of Bone and Joint Degeneration DiseasesProvincial Key Laboratory of Bone and Joint Degeneration DiseasesProvincial Key Laboratory of Bone and Joint Degeneration DiseasesProvincial Key Laboratory of Bone and Joint Degeneration DiseasesProvincial Key Laboratory of Bone and Joint Degeneration DiseasesDepartment of Rheumatology and ImmunologyProvincial Key Laboratory of Bone and Joint Degeneration DiseasesDiffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damage the vascular endothelium and aggravate vascular inflammation, which is considered an important pathogenic factor of DAH in SLE. Therefore, blocking the release of NETs from neutrophils is an important target for the treatment of DAH in SLE. In this study, we investigated whether the inhibition of neutrophils releasing NETs could relieve DAH in SLE. Necrostatin-1 (Nec-1), a small molecule, has been reported to inhibit the release of NETs by neutrophils. In vitro experiments revealed that Nec-1 inhibited alveolar epithelial cell damage by preventing the release of NETs. Furthermore, vivo studies showed that Nec-1 alleviated lupus pulmonary haemorrhage in mice by reducing lung pathology severity, body weight, and serum inflammatory cytokine levels. Mechanistically, Nec-1 prevented NET release by inhibiting neutrophil elastase (NE) activation and N-Gasdermin D (N-GSDMD) expression. Additionally, immunohistochemistry and immunofluorescence findings showed that Nec-1 decreased NE expression in the lung tissues of mice with lupus pulmonary haemorrhage. Thus, NETs released by neutrophils contributed to the pathogenesis of DAH in SLE, and Nec-1 showed protective effects by the inhibition of NET production via the reduction of NE activation and N-GSDMD expression.http://dx.doi.org/10.1155/2023/4743975 |
| spellingShingle | Xinai Han Xiaoming Zhang Rui Song Shiqi Li Shujing Zou Quanguang Tan Tianyang Liu Shugeng Luo Zhe Wu Hongyu Jie Jinhong Wang Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus Journal of Immunology Research |
| title | Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus |
| title_full | Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus |
| title_fullStr | Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus |
| title_full_unstemmed | Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus |
| title_short | Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus |
| title_sort | necrostatin 1 alleviates diffuse pulmonary haemorrhage by preventing the release of nets via inhibiting ne gsdmd activation in murine lupus |
| url | http://dx.doi.org/10.1155/2023/4743975 |
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